Pediatric and adult patients who develop influenza virus are at increased risk of secondary local and systemic bacterial and fungal infections. Previous studies have shown that when human peripheral blood polymorphonuclear leukocytes (PMNL) are incubated with influenza virus there is depression of end stage PMNL functions (i.e., chemotactic, oxidative and secretory). Recent data indicate that: 1) virus-induced inhibition of lysosome-phagosome fusion is responsible for the end stage PMNL dysfunction, 2) THE VIRUS IS INTERFERING WITH ACTIN POLYMERIZATION TO SUBSEQUENT STIMULI AT EARLY TIME POINTS (i.e. WITHIN 15 SEC.) AND 3) THE ISOLATED HEMAGGLUTININ COMPONENT OF THE VIRUS CAN CAUSE END-STAGE DYSFUNCTION IN PMNL. This project will investigate the mechanism by which the virus disrupts PMNL function by determining whether the virus: 1) is altering activation steps (e.g., calcium regulation at the plasma membrane or in the cytosol, or 2) interfering with processes (e.g., NADPH oxidase activation) occurring in the phagosome/lysosome. In addition, studies will be done to determine if the virus is interfering with cytoskeleton function either by direct attachment of viral components to cytoskeletal elements or by interfering with preliminary steps necessary for polymerization and depolymerization of the cytoskeleton. Other studies will be done to determine which properties of the virus are responsible for depressed PMNL function. These experiments will involve further testing of the effect on the cell of specific components of the virus which have been separated from the intact virus; studies will examine the effect of hemagglutinin and other virus components on activation steps, cytoskeleton functions and end- stage functions which are known to be abnormal in PMNL treated with intact virions. Other studies will compare the properties of depressing virus and non-depressing virus preparations and searching for factors released from virus infected cells which cause PMNL dysfunction. While these studies are designed to determine the mechanism(s) by which influenza virus alters PMNL function, the virus should also serve as a useful probe in better understanding normal PMNL function. An increased understanding of how influenza virus causes phagocytic cell dysfunction will expedite the development of therapies to decrease the morbidity and mortality due to superinfections induced by influenza and other viruses.